KR20190129059A - Pharmaceutical composition - Google Patents

Abstract

The present invention comprises a synergistic binding of vitamin D or derivatives thereof or precursors thereof and hyaluronic acid or derivatives thereof encapsulated in a lipid based colloidal carrier system (preferably lipid based vesicles such as liposomes, nisosomes, transferosomes). For the prevention and / or treatment of inflammatory skin and mucous membranes as well as novel compositions and topical formulations thereof, in particular for the prevention and / or treatment of skin photodamage, in particular of skin erythema (skin inflammation) and actinic keratosis, as well as non-melanoma skin cancer To its use in prophylaxis and / or treatment.

Description

Pharmaceutical composition

The present invention provides a synergistic combination of vitamin D or derivatives thereof or precursors thereof and hyaluronic acid or derivatives thereof encapsulated in a lipid based colloidal carrier system (preferably lipid based vesicles such as liposomes, nisosomes, transferosomes). New compositions and topical formulations thereof, as well as the prevention and / or treatment of inflammatory skin and mucous membranes, in particular the prevention and / or treatment of skin photodamage, in particular skin erythema (skin inflammation) and actinic keratosis To its use in the prevention and / or treatment of melanoma skin cancer.

Skin disorders according to ICD-10 (International Classification of Diseases, Version 2016) include: (a) a group of symptoms in which the skin becomes inflammatory, blisters, and hard, thick, and scaled (prolonged over a long period of time; , Including (e) eczema causing burns and itching), (b) any type of skin inflammation, (c) inflammatory processes affecting the skin (with signs of red rash, itching, and blistering), e.g. Contact dermatitis, atopic dermatitis, seborrheic dermatitis and psoriasis, and (d) papillary vesicle dermatitis of pruritus, which occurs in response to many endogenous and exogenous agents. Photodamage of the skin (according to ICD-10 version 2016) has the following main symptoms: skin atrophy, skin pigmentation (patch / spot), photodermatitis (erythema: inflammatory, reddening skin), capillary dilator (couperose )) And skin disorders due to radiation of ultraviolet A (UVA) and ultraviolet B (UVB) with actinic keratosis. UVB with a wavelength of 280-315 nm provides the skin with the energy required to make vitamin D3, but is also a primary mutagen that penetrates the epidermal layer of the skin, potentially causing skin cancer (non-melanoma skin cancer (NMSC) and melanoma). Resulting in DNA mutations leading to. These mutations may be clinically related to an increase in specific signs of light damage such as elastin and collagen defects leading to skin atrophy. UVA with a wavelength of 315-400 nm can penetrate deeper into the skin as compared to UVB and thus damage both the epidermal and dermal layers. With constant UVA exposure, the size of the dermal layer will be reduced, causing atrophy of the skin. Potential damage can lead to indirect damage or capillary distension (Copprose), as well as lipids and proteins, as well as cellular DNA of the skin barrier through the generation of cytotoxic reactive oxygen species (ROS), including dilated or broken blood vessels do. Exposure to both UVA and UVB can also cause inflammation, including clinically specified as capillary dilator (Copprose) and photodermatitis (erythema causing inflammatory and reddening skin), pigmentation (patch / spot) and other skin disorders. Can lead to vasodilation (see, eg, references 1, 2, 3).

In inflammatory skin tissues, high levels of reactive oxygen species (ROS), such as nitric oxide, are present. Nitric oxide (NO) is further reacted with oxygen (O ₂ ) with peroxynitrite (ONOO ⁻ ). Peroxynitrite and its degradation (NO ₂ ⁻ and CO ₃ ⁻ ) from reaction with CO ₂ are highly cytotoxic throughout the oxidation of lipids, proteins and DNA in the epidermis.

Various approaches have been proposed to prevent skin inflammation such as photodamage and its effects, including the use of vitamins such as vitamin D3 and derivatives and precursors thereof, as well as hyaluronic acid and the like.

Vitamin D is the most important vitamin D ₃ in humans (Or cholecalciferol) and vitamin D ₂ (Or ergocalciferol). Typically, vitamin D3 is obtained by UVB photolysis of 7-dehydrocholesterol (or 7-DHC, remarkably found at about 25-50 ug / cm 2 in the basal and visible layers of the upper layers of the skin) See reference 4-7, FIG. 1] Precursor previtamin D3 is obtained, which is then thermally isomerized to give vitamin D3. Vitamin D3 production throughout the skin is known to decrease dramatically with ageing (up to 75 wt% at age 70). Vitamin D3 and its precursors and derivatives are biologically very active. For example, precursor 7-DHC has the ability to bind reactive oxygen species NO and thus avoids overproduction of cytotoxic peroxynitrite to the top part of the skin, thus preventing a vicious cycle of skin inflammation with skin damage to cells. 2, 3. Vitamin D3 plays a role in many processes, including bone mineralization, bone growth and bone remodeling, regulation of cell growth, neuromuscular and immune function, and others. Certain vitamin D3 analogs (for example 25-hydroxy-vitamin-D3 or calcidiol, 1,25-dihydroxyvitamin-D3 or calcitriol, calcipotriol; see eg 8, 9, 10, FIG. 3) It has also been suggested that can be used topically to treat skin conditions, including psoriasis (see, eg, references 11, 12, 13, 14). In addition, recent studies using genetically modified mice, which show altered mineral homeostasis due to high vitamin D3 activity, have characterized features of premature tract including delayed growth, osteoporosis, atherosclerosis, ectopic calcification, immunological deficiency, skin and general organ atrophy Indicated. This and other findings suggest that serum calcidiol may be associated with an increased risk of aging-related chronic diseases including cancer. Vitamin D is also involved in rebuilding the skin barrier [see, for example, reference 15, FIG. 2] to maintain immune defense against microorganisms and to protect healthy microflora [see, for example, reference 16], vitamin D3 Also reduces inflammation, supports skin, participates in wound healing (see, eg, Ref. 17-20), and protects the skin from light damage [see, for example, Ref. 21-25, FIGS. 2, 3). Reference]. Overall, it is estimated that the local production of vitamin D in the skin along with the browning of the skin is the most important mechanism of skin protection against light damage [see, for example, reference 26].

Hyaluronic acid (HA) is a linear polysaccharide with repeating disaccharide units composed of glucuronic acid and N-acetyl glucosamine and is one of the major matrix substances in which the cellular and fibrous components of the matrix, such as collagen and elastin, are embedded. See, eg, references 27, 28, FIG. 2]. HA has an enormously high water binding capacity [see eg 29] and contributes greatly to the maintenance of extracellular space and to control tissue hydration that acts as a humectant [see for example 30]. Crosslinked HA polymer chains are known to convert HA solutions to gels. Crosslinker molecules combine the individual HA polymer chains to form a clear network macroscopically into agglomerates. It has been suggested that HA plays a pivotal role in tissue regeneration (see, eg, references 31, 32, FIG. 2).

However, despite the numerous formulations commercialized for the treatment of skin, it is possible to prevent and / or treat the symptoms of general skin inflammation, in particular light damage, ie the affected skin, and even more, skin caused by sun exposure, especially UV radiation. There is still a high demand for formulations that can prevent damage with greater effectiveness.

Applicants have now found that vitamin D3 or a derivative or precursor thereof, preferably a precursor such as 7-dehydrocholesterol (7-DHC) or a derivative thereof, can be formulated in combination with HA in a stabilized colloid. Carrier systems of this colloid include inflammatory skin, especially light damage of the skin such as skin atrophy, skin pigmentation (patches / spots), photodermatitis (erythema: inflammatory and reddening skin), capillary dilator (cooperrose) and UV It has a synergistic effect on the treatment and prevention of prophylaxis to avoid skin erythema and actinic keratosis [FIG. 2].

The Applicant therefore proposes a lipid based colloidal carrier system (preferably to allow penetration and localized delivery of stabilized vitamin D3 or derivatives or precursors thereof, preferably precursors such as 7-DHC or derivatives thereof into the upper layer of the skin (preferably Vitamin D3 or a derivative or precursor thereof, preferably a precursor such as 7-DHC or a derivative thereof and HA or a derivative, optionally encapsulated in a lipid-based vesicle such as liposomes, niosomes, transferosomes), optionally in combination with additional excipients It provides a novel composition comprising.

Two topically combined active substances directly synergize directly to the upper layer of skin, particularly on the predominant disorder of inflammatory skin in light damage, in particular on the signs according to the ICD-10 of the sun and in particular UV radiation exposed and damaged skin. It can work in a way. Thus, the novel composition of the present invention can overcome the disadvantages of the prior art. An additional seven excipients will synergize with the two active agents and will enable optimal efficacy in preventing and / or treating the described skin disorders. The described compositions (and formulations thereof) will provide a novel approach to prevent and / or treat most disorders of inflammatory skin, sun and especially UV radiation damaged skin [FIGS. 2, 3].

In a first aspect, the invention relates to at least one vitamin D3 or derivative or precursor thereof, preferably encapsulated in a lipid based colloidal carrier system (allowing optimal skin penetration and stabilization of vitamin D3 or a precursor or derivative thereof). Is for novel compositions (also called compositions of the present invention) and suitable formulations thereof which comprise synergistic binding of precursors such as 7-DHC or derivatives thereof and at least one HA or derivatives thereof. By encapsulating on oil (or lipid), vitamin D3 or its precursors or derivatives (and especially 7-DHC or its derivatives) is stabilized and unwanted reactions (such as oxidation or other degradation reactions) are eliminated. Lipid based colloidal carrier systems allow vitamin D3 (and inactive vitamin D3 precursors such as 7-DHC or derivatives thereof) to enter the upper layer of skin exerting its activity (after conversion to active vitamin D3 by UVA and UVB exposure). Allow it to penetrate.

In a preferred embodiment vitamin D3 is a vitamin D3 precursor such as 7-DHC or a derivative thereof, and the composition of the present invention is a vitamin D precursor such as 7-DHC or a derivative thereof in combination with HA or a derivative thereof encapsulated in a lipid based colloidal carrier system. It includes. Vitamin D (and especially vitamin D3 precursors such as 7-DHC or derivatives thereof) is preferably present in the colloidal carrier system at a final concentration of 0.01 to 0.5 wt%.

In another embodiment the composition is one selected from vitamin A (preferably retinyl palmitate), at least one vitamin B, vitamin C (preferably L-ascorbic acid) and vitamin E (preferably tocopheryl acetate) More preferably, it further contains 1, 2, 3, 4, 5, 6, 7 additional components. Preferably, the composition comprises (i) retinyl palmitate (vitamin A), (ii) riboflavin (vitamin B2), (iii) niacinamide (vitamin B3), (iv) dexpanthenol (provitamin B5), ( v) at least one, most preferably all of folic acid (vitamin B9), (vi) L-ascorbic acid (vitamin C) and (vii) tocopheryl acetate (vitamin E).

In another specific embodiment, the lipid based colloidal carrier system is a liposome carrier system (preferably lipid based vesicles such as liposomes, niosomes, transferosomes) consisting of at least one phospholipid and at least one fatty acid. Preferably the lipid based colloidal carrier system comprises, for example, one or more of lecithin, linolenic acid, linoleic acid, phosphatidylcholine and caprylic / capric triglycerides.

In a preferred embodiment, the lipid based colloidal carrier (e.g. lipid based vesicles such as liposomes, niosomes, transferosomes) comprises two lipophilic agents, retinyl palmitate (vitamin A), tocopheryl acetate (vitamin E) And 7-DHC and HA in combination with five hydrophilic agents, riboflavin (vitamin B2), niacinamide (vitamin B3), dexpanthenol (provitamin B5), folic acid (vitamin B9), L-ascorbic acid (vitamin C) Synergistic binding.

The lipophilic formulation is encapsulated in a bilayer or multilayer system, while the hydrophilic formulation is encapsulated in the aqueous phase. Thus, in one embodiment, the compositions of the present invention (i) encapsulate vitamin D3 (and especially vitamin D3 precursors such as 7-DHC or derivatives thereof) on an oil (or lipid) of a lipid based colloidal carrier system at room temperature, And (ii) by separately preparing HA in the aqueous phase. The composition is obtained by emulsification of the oil (or lipid) phase and the aqueous phase (by mixing at room temperature or by spontaneous integration). Preferably, the particles will have a diameter of 10-500 nm, more preferably 10-300 nm, most preferably 20-150 nm.

In a further aspect, the compositions of the present invention are in the form of various formulations suitable for topical or transdermal and mucosal administration. These topical formulations contain the pharmaceutical compositions of the invention as well as additional adjuvants such as buffers, preservatives and the like. Typical formulations include hydrogels, lyogels, hydro lotions, lipotions, creams, ointments, and the like.

In a further aspect, the invention relates to the prevention and / or treatment of skin light damage symptoms, in particular skin atrophy, skin pigmentation (patches / spots), photodermatitis (erythema: inflammatory and reddening skin), capillary dilator (Copprose) ), The use of the compositions (and topical formulations thereof) in the prevention and / or treatment of photodermatitis (erythema: inflammation of the skin), prevention of actinic keratosis and protection of skin UVA and UVB.

1: Appropriate concentrations of inactive precursor 7-DHC are transported in the form of lipid-based colloids according to the invention in the upper layer of the skin, where it is converted to active vitamin D3 by UVA and UVB exposure.
2: 7-DHC in the oil (or lipid) phase and hyaluronic acid (HA) in the aqueous phase are integrated into a colloidal carrier system that allows penetration into the upper layer of the skin. Activation and synthesis of vitamin D3 from 7-DHC can block the pathway of skin damage by solar UVA / UVB. Inactive 7-DHC is further protected at oxidative processes by encapsulation in a carrier system and additionally at the target into the upper layer of skin having a strong function of eliminating cytotoxic ROS such as peroxynitrate resulting from the oxidative process of nitrates. Only active. This scavenger function of overproduced NO enables protection of skin damage from UVA / UVB.
3: 7-DHC pathway of potent anti-inflammatory activity in the upper layer of skin after activation with vitamin D3

In a first aspect, the present invention provides at least one vitamin D3 or a precursor or derivative thereof, preferably a precursor such as encapsulated in a lipid based colloidal carrier system (preferably lipid based vesicles such as liposomes, niosomes, transferosomes). Novel compositions and suitable topical formulations thereof, hereinafter also referred to as the compositions of the present invention, comprising 7-dehydrocholesterol (7-DHC) or derivatives thereof, and synergistic binding of at least one HA or derivatives thereof It is about. All definitions and embodiments specified below apply to compositions (and topical formulations) and uses thereof of the invention (unless otherwise specified). The term “topical” as used herein refers to administration to any part of the skin and mucous membranes, including the ocular mucosa. The term “photodamage” as used herein refers to ICD-10 Definitions 2016 and features skin disorders due to sun exposure and radiation of UVA and UVB. The term "senergistic" when used in connection with the compositions of the present invention means that the therapeutic effect of the binding of the agent is greater than the sum of the effects of the individual agents in the binding.

The term "vitamin D" as used herein refers to any form of antirespiratory disease known in the art as suitable for nutritional use such as vitamin D ₁ , vitamin D ₂ , vitamin D ₃ , vitamin D ₄ , vitamin D ₅ , vitamin D ₆ , and vitamin D ₇ . Preferred is “vitamin D3”, as used herein, which includes 1a-hydroxyvitamin D3, which can be converted metabolically in humans with a compound that activates the vitamin D receptor or activates the vitamin D receptor, Vitamin D3 as well as precursors of vitamin D3, such as 7-DHC (provitamin D3) or derivatives thereof, or derivatives of vitamin D3, such as 25-hydroxyvitamin D3, or 1a, 25-dihydroxyvitamin D3. Preferred is 7-DHC. Vitamin D, preferably vitamin D3 and its precursor 7-DHC, are used at concentrations of 10,000 IU-50,000 IE and 0.01-4 wt%. According to the invention, the preferred concentration is 0.01 to 3 wt%, more preferably 0.01 to 0.75 wt%, most preferably 0.01 to 0.5 wt% of the total weight of the composition.

The term "hyaluronic acid" (also known as hyaluronan, hyaluronate, or HA) as used herein refers to N- linked together by alternating beta-1,4 and beta-1,3 glycoside bonds. It refers to unsulfated glycosaminoglycans composed of repeating disaccharide units of acetylglucosamine (GlcNAc) and glucuronic acid (GlcUA). The term "hyaluronic acid" or "HA" as used herein refers to HA or salts of HA, such as sodium, potassium, magnesium and calcium salts, among others. The term "hyaluronic acid" or "HA" includes combinations of these natural and synthetic formulations, including both natural and synthetic formulations and salt forms thereof. HA and its various molecular size fractions and their respective salts are particularly useful as agents in the treatment of arthrosis, as adjuvant and / or alternative agents for natural organs and tissues, especially in ophthalmology and plastic surgery, and as agents in cosmetic preparations. Used. HA's products have also been developed for use in orthopedics, rheumatology and dermatology. High molecular weight (MW) fractions of HA having an average MW of about 1 to about 1.5 MDa are well known for providing excellent moisturizing properties in cosmetic compositions such as lotions and creams. Ultra low MW fractions of HA have been reported to have a higher ability to penetrate the skin barrier.

In a preferred embodiment, crosslinkers (eg 1,4-butanediol diglycidyl ether (BDDE) and other homogeneous ones) can be used to bind the HA polymer chains to each other, converting the liquid HA solution into a gel. Let's do it. Thus, in certain embodiments, the HA exhibits high water retention into the skin, through the HA polymer chain (via the primary hydroxyl site (-CH ₂ OH) and / or secondary hydroxyl site (-CHOH) in the HA monomer unit). In the form of a gel obtained by crosslinking with low molecular crosslinked HA.

HA for use in the present invention is preferably between 4 kDa and 50 kDa in combination with low MW, for example higher MW up to 200,000 kDa. Typically, HA is 0.01 to 8 wt% (or 80 mg / ml), preferably 0.01 to 5 wt% (or 50 mg / ml), more preferably 0.01 to 4 wt% (or 40 mg / ml), most Preferably at a concentration of 0.01 to 3 wt% (or 30 mg / ml). The most preferred concentration of total HA is 3 wt%, preferably a mixture of lowest MW HA of 4-5 kDa, low to medium or intermediate molecules HA of 40-50 kDa and high MW HA of 50,000-200,000 kDa (wt%). It becomes Preferably the ratio of the lowest MW HA of 4-5 kDa to the middle molecule HA of 40-50 kDa to the high MW HA of 50,000-200,000 kDa is (1-10) :( 0.1-2) :( 0.1-2), Preferably (2-6) :( 0.5-1.5) :( 0.5-1.5), most preferably about 4: about 1: about 1 (or approximately equivalent wt% of medium and high MW HA). Thus, most preferred is a 3 wt% HA mixture of 2 wt% lowest molecular HA of 4-5 kDa, 0.5 wt% of 40-50 kDa low to medium or intermediate molecule HA and 0.5 wt% of 50,000-200,000 kDa high MW HA.

In combination with vitamin D, such as vitamin D3 such as 7-DHC, HA has a synergistic effect on hydration of the epidermis and also on immunoprotective effects [see, for example, References 33, 34, 35, 36 FIGS. 2, 3 Reference]. HA, along with vitamin D3 such as 7-DHC, has a synergistic physico-chemical mode of action for light damaged skin.

Thus, in a preferred embodiment the composition of the present invention comprises 7-DHC on the oil of the colloidal carrier system and HA as the active substance on the aqueous phase of the colloidal carrier system. The two phases are obtained separately and then combined to form a lipid based colloidal carrier system.

It has further been found that 7-DHC also acts as an additional active agent of additional ingredients (hereinafter also referred to as adjuvants) that are particularly effective in the prevention and / or treatment of photodamage. In particular, it further comprises at least one component selected from vitamin A (preferably retinyl palmitate), at least one vitamin B, vitamin C (preferably L-ascorbic acid) and vitamin E (preferably tocopheryl acetate) It was found that the compositions to achieve effective prophylaxis and / or treatment of photodamage [see FIGS. 1, 2, 3].

Thus in certain embodiments the compositions of the present invention comprise vitamin A (preferably retinyl palmitate), at least one vitamin B, vitamin C (preferably L-ascorbic acid) and vitamin E (preferably tocopheryl acetate) It further comprises one or more, preferably 1, 2, 3, 4, 5, 6, or 7 additional components selected from.

The term "vitamin A" as used herein refers to retinol, retinal, retinic acid, and several provitamin A carotenoids (most notably beta-carotene), preferably the main form retinyl palmitate. Vitamin A and especially retinyl palmitate absorb light in the short-wavelength UVA range, having a photoprotective effect in the skin. It has been found that retinyl palmitate has an additive effect with 7-DHC on absorbing short-wavelength UVA ranges, down regulation of NF-κB and thus UV-induced inflammation of the skin [see, for example, see See Documents 36 and 37. Retinyl palmitate diffuses into the skin, where it partially hydrolyzes to retinol, penetrates into the stratum corneum, epidermis, and dermis and acts as a UV filter by absorbing UV radiation in the range between 300-350 nm. Thereby supporting the effect of the composition of the present invention. Typically, retinyl palmitate is used at a concentration of 0.01 wt% to 2 wt%, preferably 0.01 wt% to 0.5 wt%, more preferably 0.01 to 0.2 wt%, most preferably 0.01 to 0.1 wt%. .

The term "vitamin B" as used herein refers to thiamine (B1), riboflavin (B2), niacin (B3), pantothenic acid (B5), pyridoxine (B6), folate (B7) and various cobalamin (B12) It refers to a class of chemically distinct vitamins that are soluble in water. In one embodiment the term “vitamin B” as used herein refers to riboflavin (B2). Typically, riboflavin is from 0.01 wt% to 2 wt%, preferably 0.01 wt% to 0.2 wt%, more preferably 0.01 wt% to 0.1 wt%, most preferably 0.01 wt% of the total weight of the composition according to the invention. % To 0.0.05 wt%. In another embodiment, the term “vitamin B” as used herein refers to niacinamide. Niacinamide, an amide of niacin (B3), is a hydrophilic endogenous substance that can act as an antioxidant, improve epidermal barrier function, reduce skin hyperpigmentation, reduce skin atrophy, and redness / stain Decreases skin mass and improves skin elasticity [54, 55]. Niacinamide has a synergistic effect with HA as a wetting agent of the epidermis and in reconstructing the structural and functional integrity of the epidermal barrier function [FIG. 2]. Niacinamide controls NFκB-mediated transcription of signaling molecules by inhibiting nuclear poly (ADP-ribose) polymerase-1 (PARP-1). In addition niacinamide will have an added effect on NFκB-mediated transcription with 7-DHC and vitamin A (particularly retinyl palmitate) (see, eg, references 38, 40). Typically, niacinamide (vitamin B3) is in a concentration of 0.5 wt% to 5 wt%, preferably at most 4 wt%, more preferably at most 3 wt%, most preferably 3 wt% of the total weight of the composition according to the invention. Used.

In another embodiment, the term “vitamin B” as used herein refers to dexpanthenol (provitamin B5). Topical dexpanthenol acts as a humectant and activity can be based on the hygroscopic properties of dexpanthenol. Dexpanthenol further exhibits a protective effect on skin irritation (see, eg, Reference 39). Dexpanthenol significantly accelerates the wound healing process in pediatric post-tonsilectomy interventions (see, eg, Reference 36). Typically, dexpanthenol (vitamin B5) is used at a concentration of 0.5 wt% to 5 wt%, preferably 3 wt%, more preferably 2.5 wt%, most preferably 1 wt% of the total weight of the composition according to the invention. do.

In further embodiments the term “vitamin B” as used herein refers to folic acid (B9). Folic acid is essential for DNA synthesis, repair and methylation, in particular nucleotide biosynthesis and remethylation of homocysteine. Folic acid is essential for the production of cellular DNA, RNA and is known for its use in the prevention of neural tube defects (NTDs) and severe birth defects and in the treatment of anemia caused by folic acid deficiency. Folic acid also exhibits a significant acceleration of epidermal skin regeneration in vitro and in vivo in combination with creatine [see, for example, Reference 41] and thus synergistic effect with 7-DHC covering UV-induced cell damage and inflammation Can promote [FIG. 2]. Typically, folic acid (vitamin B9) is present in a concentration of 0.01 wt% to 0.2 wt%, preferably 0.07 wt%, more preferably 0.05 wt%, most preferably 0.02 wt% of the total weight of the composition according to the invention. Used as

The term "vitamin C" as used herein refers to L-ascorbic acid used as a supplement to treat and prevent scurvy and erythema of the skin (see, eg, references 42, 43). Scurvy causes the formation of brown spots on the skin, sponge gums, and bleeding from all mucous membranes. L-ascorbic acid is essential for the hydroxylation of proline and lysine in the synthesis of collagen (see, eg, references 44, 45, 46) and for the transport of fatty acids into the mitochondria for ATP production in dermal cells, the synthesis of carnitine While required in [see, eg, references 47, 48], it acts as an electron donor for different essential enzymes in the skin. Ascorbate also acts as an antioxidant, protecting against oxidative stress [see, for example, Reference 49] and being a powerful reducing agent capable of quickly eliminating numerous reactive oxygen species (ROS) and hence with 7-DHC Promote synergistic effects. Typically, L-ascorbic acid is used at a concentration of 0.1 wt% to 10 wt%, preferably 5 wt%, more preferably 2 wt%, most preferably 3 wt% of the total weight of the composition according to the invention.

The term "vitamin E" as used herein refers to a compound known as tocopherol and tocotrienol, preferably tocopheryl acetate. Tocopheryl acetate can penetrate the skin and into living cells, where about 5 wt% is converted to free tocopherol. Tocopheryl acetate has shown antioxidant activity and acts as a peroxyl radical scavenger, making it impossible to produce damaging free radicals in tissues [see, for example, reference 50] and thus enhancing synergistic effects with 7-DHC can do. Typically, tocopheryl acetate is 0.1 wt% to 5 wt%, preferably 0.1 wt% to 5 wt%, more preferably 0.1 wt% to 3 wt%, most preferably 0.1 wt% of the total weight of the composition according to the present invention. It is used at a concentration of% to 2 wt%.

Thus, in a preferred embodiment, the compositions of the present invention comprising 7-DHC and HA are retinyl palmitate, riboflavin, niacinamide, dexpanthenol, folic acid, L-ascorbic acid and encapsulated in a lipid based colloidal carrier system. Further comprises one or more components selected from tocopheryl acetate. In certain embodiments the compositions of the present invention comprise 7-DHC and HA, as well as combinations of the following components:

a) retinyl palmitate and riboflavin or retinyl palmitate and niacinamide or retinyl palmitate and dexpanthenol or retinyl palmitate and folic acid or retinyl palmitate and L-ascorbic acid or retinyl palmitate and tocopheryl acetate .

b) riboflavin and niacinamide or riboflavin and dexpanthenol or riboflavin and (v) folic acid or riboflavin and L-ascorbic acid or riboflavin and tocopheryl acetate.

c) Niacinamide and dexpanthenol or niacinamide and folic acid or niacinamide and L-ascorbic acid or niacinamide and tocopheryl acetate (vitamin E).

d) dexpanthenol and folic acid or and L-ascorbic acid or dexpanthenol and tocopheryl acetate.

e) folic acid and L-ascorbic acid or folic acid and tocopheryl acetate.

f) L-ascorbic acid and tocopheryl acetate.

Most preferably, the compositions (and topical formulations) of the invention comprising 7-DHC and HA are component retinyl palmitate, riboflavin, niacinamide, dexpanthenol, folic acid, L, encapsulated in a lipid based colloidal carrier system. -Ascorbic acid and tocopheryl acetate further. The most preferred concentrations and ranges of concentrations are listed in Table 1 below.

The active ingredient is incorporated into the colloidal carrier system according to the invention (typically: water:> 50 wt%, for example 50-75 wt%; carrier system 10 wt%; additional oily ingredients, preservatives, buffers, Filter, 5-25wt%)

The term "lipid based colloidal carrier (system)" (or "colloid") as used herein refers to a well known particulate carrier system, preferably spherical vesicles having at least one lipid bilayer. Typical colloidal carriers include liposomes, niosomes, transferosomes, colloids, nanoparticles, microemulsions and others, preferably liposomes, niosomes, transferosomes, most preferably liposomes. Depending on its size and the number of bilayers, lipid based colloidal carrier systems are: (a) multilayer vesicles (MLV), (b) large single lamella vesicles (LUV), (c) small single lamella vesicles (SUV) and (d) multivesicular vesicles (MW), oligolamellar vesicles (OLV). Preferred particle sizes range from 10-500 nm, preferably from 10-300 nm, more preferably from 20-150 nm.

In certain embodiments, the colloid is based on natural and / or synthetic phospholipids and typically constitutes 10 wt% of the formulation. Phospholipids typically used are in the fats linked together by phosphate-containing polar end groups and glycerol molecules (eg glycerophospholipids) or sphingosine molecules (eg phosphosphingolipids) which are hydrophilic and thus soluble in water. Fatty acids having soluble hydrophobic end groups.

In some embodiments, the phospholipid used in the colloidal carrier system includes one or more of phosphatidylcholine, lysophosphespotidylcholine, hydrogenated phospholipids, and unsaturated phospholipids. Examples of glycerophospholipids include phosphatidic acid (phosphatidate) (PA), phosphatidylethanolamine (cephalin) (PE), phosphatidylcholine (lecithin) (PC), phosphatidylserine (PS), and phosphinositide And further include phosphatidylinositol (PI), phosphatidylinositol phosphate (PIP), phosphatidylinositol bisphosphate (PIP2), and phosphatidylinositol triphosphate (PIP3). Examples of phosphorphosphingolipids include ceramide phosphorylcholine (sphingomyelin) (SPH), ceramide phosphorylethanolamine (sphingomyelin) (Cer-PE), and ceramide phosphorylglycerol. The colloidal carrier system of the present invention may further comprise fatty acids such as omega-3, omega-6 and omega-9 fatty acids. Preferred examples used in the present invention are lecithin, sphingomyelin, phosphatidylcholine, linoleic acid, linolenic acid, caprylic acid, capric acid, lupine albus seed oil, squalene, imidazolidinyl urea and sodium ascorbyl phosphate. Preferred embodiments of the lipid based colloidal carrier system are shown in Table 2.

In further embodiments, the colloidal carrier system may also comprise polycarbonate, polyvinylpyrrolidone (PVP), and also copovidone of polyvidone or povidone membranes, preferably MW 10 nm-500 nm. Copovidone can be used as membrane-forming agents and binders and also as carrier systems.

For use in the present invention, the lipophilic formulation will be encapsulated in a bilayer system, while the hydrophilic formulation will be encapsulated in the aqueous phase of the system. Thus, vitamin D precursors (such as 7-DHC or derivatives thereof) and phospholipid (s) and optional additional lipophilic agents (such as retinyl palmitate and tocopheryl acetate) are thus added to the oil phase of the colloidal carrier system at room temperature. It is directly incorporated into. In separate steps, the HA and optional additional hydrophilic agents (eg riboflavin, niacinamide, dexpanthenol, folic acid, L-ascorbic acid) are mixed together separately in aqueous solution. Aqueous solutions comprising HA and optional additional hydrophilic agents are mixed onto an oil phase comprising a vitamin D precursor (such as 7-DHC or a derivative thereof). After emulsification of the two phases, the hydrophilic component of the composition (HA and additional hydrophilic agent) is present in the aqueous compartment, while the lipophilic component of the composition is already inserted itself in a first step into the phospholipid bilayer of the particles.

Thus, in the most preferred embodiment, the lipid based colloidal carrier system (preferably lipid based vesicles such as liposomes, niosomes, transferosomes) comprises component vitamin D3 such as 7-DHC or derivatives thereof, and optionally HA and optionally Lecithin, infused with at least one, preferably 1, 2, 3, 4, 5, 6 or 7 of the components retinyl palmitate, riboflavin, niacinamide, dexpanthenol, folic acid, L-ascorbic acid and tocopheryl acetate Linolenic acid, linoleic acid, phosphatidylcholine and papryl / papr triglycerides. The uniquely charged and stable carrier system will enable the skin to penetrate the upper layer of skin so that the synergistic compositions of the present invention can directly effect the desired site.

Depending on the nature and type of application, the compositions of the present invention may further comprise one or more pharmaceutically acceptable additives, excipients, adjuvants commonly used in formulations used for application to the skin and / or mucous membranes. Can be.

Typical additives are, for example, related UV filter systems for the prevention of photodamage and protection of solar UVA and UVB or one or more UVA / B protecting agents such as filaggrin trans-urocanine acid, butyl methoxydibenzoylmethane Neo Heliopan 357 Eusolex 9020, Parsol 1789, methylene bis-benzotriazolyl tetramethylbutylphenol (nano), Tinosorb M, ethylhexyl triazone uvinul T 150, bis-ethylhexyloxyphenol methoxyphenyl triazine Tinosorb S, ethylhexyl methoxycinnamate uvinul MC 80, Parsol MCX, Neo Heliopan AV 4, and others. UV filter (s) are incorporated into the active and auxiliary components for the prevention of cutaneous erythema and actinic keratosis, or other forms of non-melanoma skin cancer (NMSC).

Typical adjuvants include, for example, surfactants, emulsifiers, emollients, thickeners, conditioning preservatives, buffers, wetting agents, fragrances, and the like. Thus, the carrier system may further comprise one or more surfactants. The term "surfactant" refers to a substance that lowers the surface tension of a liquid and the interfacial tension between the two liquids, allowing for easier dispersion thereof. The surfactant has a hydrophilic head that attracts water molecules and a hydrophobic tail that attracts water and at the same time attracts itself to oil and grease from dust. These opposing forces have the ability to loosen dust and suspend it in water, removing dirt from surfaces such as human skin, fibers and other solids when the surfactant is dissolved in water. Examples of suitable surfactant formulations include, but are not limited to, non-ionic, ionic (anionic or cationic) or zwitterionic (or amphoteric, wherein the head of the surfactant contains two opposite charge groups). Include. Examples of anionic surfactants include, but are not limited to, those based on sulfate, sulfonate or carboxylate anions such as perfluorooctanoate (PFOA or PFO), alkylbenzenesulfonates, soaps, fatty acid salts, or alkylsulfate salts. Such as perfluorooctanesulfonate (PFOS), sodium dodecyl sulfate (SDS), ammonium lauryl sulfate, or sodium lauryl ether sulfate (SLES). Examples of cationic surfactants include, but are not limited to, alkyltrimethylammonium, cetylpyridinium chloride (CPC), polyethers including those based on quaternary ammonium cations such as cetyltrimethylammonium bromide (CTAB), also known as hexadecyltrimethyl ammonium bromide (CTAB) Toxylated tallow amine (POEA), benzalkonium chloride (BAC), or benzethium chloride (BZT). Examples of zwitterionic surfactants include, but are not limited to, dodecyl betaine, cocamidopropyl betaine, or cotoampoglycinate. Examples of non-ionic surfactants include, but are not limited to, copolymers of alkyl poly (ethylene oxide), alkylphenol poly (ethylene oxide), poly (ethylene oxide), poly (propylene oxide) (commercially poloxamer or polox) ), Alkyl polyglucosides including octyl glucoside and decyl maltoside, fatty alcohols including cetyl alcohol and oleyl alcohol, cocamide MEA, cocamide DEA, or tween 20, tween 80, or dodecyl dimethylamine oxide It includes a polysorbate including. Preferably, the surfactant is foamed and skin friendly, such as polysorbate 20 or 40, coco glucoside, lauryl glucoside, decyl glucoside, lauryl sulfate such as ammonium, sodium, magnesium, MEA, triethyl Amines (TEA), or mipa lauryl sulfate, cocamidopropylbetaine, or sodium alkyl sulfosuccinate.

In certain embodiments the surfactant is polysorbate 10-150, which is a non-ionic surfactant commonly used as at least one polysorbate, such as excipients and emulsifiers. Preferably the polysorbate is a polysorbate-type nonionic surfactant formed by ethoxylation of sorbitan prior to the addition of lauric acid such as Scattics, PS20 such as Alkest TW 20 and Tween 20. Polysorbates stabilize the colloidal carriers and C-chains that produce efficacious and less organized crystalline structures in the presence of liquid lipids with different fatty acids provide better loading capacity for active substance acceptance. can do. The effect of polysorbate will be in stabilizing the carrier system through the physicochemical properties of the formulated nanoparticles. Colloidal carrier systems are stabilized with polysorbates such as polysorbate 20 or polysorbate 80. Polysorbate will be used as a better dispersant for liposome carrier systems. The small size and super particle surface to volume ratio can increase the loading efficiency and bioavailability of the active material, thus making the liposome carrier system a more efficient delivery system.

In another particular embodiment the surfactant is polyvinylpyrrolidone (PVP), which is known to reduce the size or prevent precipitation of the resulting particles of the active ingredient or auxiliary substance with strongly pH-dependent water solubility. PVP such as poloxamer / copovidone will be used to stabilize particles in liposome formulations. Dissolution efficiency is estimated to be increased with polyvinylpyrrolidone (PVP) and higher and increased polymer concentration. PVP is typically used as a stabilization and to increase the efficiency and bioavailability of liposome carrier systems.

Thus, in certain embodiments the carrier system is polycarbonate, polyvinylpyrrolidone (PVP), polyvidone, povidone membrane, povidone, copovidone, hypromellose and Eudragit EPO, preferably MW 10 nm-500 nm. Copovidone may be further included.

The amount of surfactant in the composition of the invention is between 0.5 and 10 wt% of the total weight of the composition according to the invention.

The term “emollients” formulation refers to an agent that softens and calms the skin to correct drying and scaling of the skin, lubricating the skin surface, promoting skin water retention, and altering product texture. Examples of suitable topical emollient formulations include, but are not limited to, octylhydroxystearate, lanolin, caprylic / capric triglycerides, cetyl palmitate, octyldodecanol, cetyl alcohol, isopropyl isostearate, glyceryl Dilaurate, isopropyl myristate, palm alcohol, dimethicone, squalane, inca pinnut seed oil seed oil, shea butter, sucrose cocoate, or mixtures thereof. Preferably the emollient is selected from the group consisting of dimethicone, squalane, incapinut seed oil seed oil, shea butter, caprylic / capric triglycerides, octyldodecanol, or mixtures thereof. The amount of emollient agent in the composition of the invention is between 10 and 30 wt% of the total weight of the composition according to the invention.

The term “wetting agent” formulation refers to a hygroscopic formulation that attracts water molecules from the surrounding environment through either absorption or adsorption, thereby preventing the skin from losing moisture. Examples of suitable topical wetting agents include, but are not limited to, glycerin, diglycerin, ethylhexylglycerin, glucose, honey, lactic acid, polyethylene glycol, propylene glycol, sorbitol, sucrose, or trealose. Preferably the humectant is selected from the group consisting of glycerin, diglycerine, ethylhexylglycerine, and mixtures thereof. The amount of wetting agent in the composition of the invention is between 0.5-15 wt%, preferably 0.5-10 wt% of the total weight of the composition according to the invention.

As used interchangeably herein, the terms "thickener" or "thickener" or "viscosity agent" refer to a substance that increases its viscosity without substantially modifying its other properties. Examples of suitable viscosities include, but are not limited to, cellulose or derivatives thereof such as hydroxypropyl methylcellulose, polyethylene glycol, microcrystalline cellulose, cetearyl alcohol, alginate, branched polysaccharides, fumed silica, xanthan gum, Carbomers, and polyacrylates. Preferably, the viscosity agent is selected from the group consisting of microcrystalline cellulose, cetearyl alcohol, cellulose, xanthan gum, and carbomer. The amount of viscosity agent in the composition of the invention is between 0.5 and 15 wt%, preferably between 0.5 and 10 wt% of the total weight of the composition according to the invention.

As used interchangeably herein, the terms "emulsifying agent" or "emulsifying agent" refer to a substance that reduces the surface tension, thereby promoting the formation of an intimate mixture of non-miscible liquids by altering interfacial tension. Emulsifiers stabilize the emulsion by increasing its kinematic stability. Examples of suitable emulsifiers include, but are not limited to, glyceryl trioleate, glyceryl oleate, acetylated sucrose distearate, sorbitan trioleate, polyoxyethylene monostearate, glycerol monooleate, sucrose Distearate, polyethylene glycol monostearate, octylphenoxypoly (ethyleneoxy) ethanol, deacyrine penta-isostearate, sorbitan sesquioleate, hydroxylated lanolin, lecithin, lanolin, triglyceryldiiso Stearate, polyoxyethylene oleyl ether, calcium stearoyl-2-lactylate, sodium lauroyl lactylate, sodium stearoyl lactate, cetearyl glucoside, methyl glucoside sesquistearate, sorbitan monopalmi Tate, methoxy polyethylene glycol-22 / dodecyl glycol copolymer, polyethylene glycol Cole-45 / dodecyl glycol copolymer, polyethylene glycol 400 distearate and glyceryl stearate, candelilla / jojoba / rice bran polyglyceryl-3 esters, cetyl phosphate, potassium cetyl phosphate, or mixtures thereof. Preferably, the emulsifier is glyceryl oleate, lecithin, sodium lauroyl lactylate, sodium stearoyl lactylate, glyceryl stearate, candelilla / jojoba / rice bran polyglyceryl-3 esters, and mixtures thereof It is selected from the configured group. The amount of emulsifier in the composition of the invention is between 0.5 and 15 wt%, preferably between 0.5 and 10 wt% of the total weight of the composition according to the invention.

The term “pH-regulated” or “buffer” formulation refers to an acid or base that can be used to adjust the pH of the final product to the desired level without affecting the stability of the solution. Examples of suitable topical pH-controlling agents include, but are not limited to acetic acid, lactic acid, citric acid, gluconic acid, ethanolamine, formic acid, oxalic acid, tartaric acid, potassium hydroxide, sodium hydroxide, triethanolamine, or mixtures thereof. Preferably, the pH-adjusting formulation is selected from the group consisting of triethanolamine, sodium hydroxide, lactic acid, and citric acid. The amount of pH-adjusting formulation in the composition of the invention is between 0.01 and 1 wt% of the total weight of the composition according to the invention.

The term “conditioning preservative” refers to a compound having a moisturizing function, more specifically a compound serving as a barrier function for the purpose of maintaining a moisturized stratum corneum, such as ceramides, sphingoid-based compounds, lecithin, glycosphingolipids, phospholipids , Cholesterol and derivatives thereof, phytosterols (Stigmasterol, β-Sitosterol or Campestrol), essential fatty acids, 1,2-diacylglycerol, 4-chromanone, cyclic triterpenes, petrolatum and lanolin; Or compounds which directly increase the water content of the stratum corneum, such as trealose and derivatives thereof, glycerol, pentanediol, pydolate, serine, xylitol, peroxyethanol, sodium lactate, glyceryl polyacrylate, ectoin and Derivatives thereof, chitosan, oligo- and polysaccharides, cyclic carbonates, N-lauroylpyrrolidonecarboxylic acid and N-α-benzoyl-L-arginine. The amount of such compounds in the compositions of the invention is from 0.001 wt% to 30 wt%, preferably 0.01 to 20 wt% of the total weight of the composition according to the invention.

The term "fragrance" refers to any perfume or aroma that can emit a pleasant odor. The fragrance substances contained in the compositions of the present invention may be derived from the aromas and aromas of natural or synthetic origin and mixtures thereof. Examples of spices and aromas of natural origin include flower extracts (lily, lavender, rose, jasmine, ylang-ylang), stems and leaves (patchouli, geranium, bitter leaves), fruits (coriander, anise, cumin, juniper), fruit Skin (bergamot, lemon, orange), roots (angelica, celery, cardamom, iris, sweet flag), timber (pine, sandalwood, driftwood, pink cedar), herbs and rice plants (taragon, lemongrass, sage, thyme) ), Needles and branches (spruce, fir, pine, why pine), resin and balsam (galburnum, gum elemi, gum benzoin, myrrh, frankincense, white cedar).

Preferably, the amount of fragrance is from 1 wt% to 30 wt% by weight, more preferably from 2 wt% to 25 wt% by weight relative to the total composition weight. Preferred compositions are shown in Table 3.

Lipid based colloidal carrier systems (eg lipid based vesicles such as liposomes, niosomes, transferosomes) can be prepared by any known technique (generally for lipid based carrier systems, see, for example, Liposomes Angel Catala, pub.InTech, 2017 (ISBN 978-953-51-3580-7), or liposome carriers are described, for example, in Liposomes, Methods and Protocols, Springer Protocols, eds.D'Souza. , Gerard GM, 2017]. For example, the colloid may be prepared by any conventional technique for preparing multilayer lipid vesicles (MLV), ie, placing one or more lipids and lipophilic vitamin D3 or precursors thereof in a suitable container, and using organic solvents, e.g. For example, by dissolving the lipid in chloroform and evaporating the organic solvent to obtain a lipid membrane. Hydration of the lipid membrane in a subsequent step is accomplished by adding an aqueous solution containing a hydrophilic component comprising hyaluronic acid. Typically the lipid suspension obtained is swirled or swirled to obtain the final composition according to the invention. Alternatively, techniques used to produce large single lamellar lipid vesicles (LUVs), such as reversed phase evaporation, infusion procedures, and detergent dilution, can be used to produce liposomes. A review of these and other methods for producing lipid vesicles can be found in the text [Liposome Technology, Volume I, Gregory Gregoriadis Ed., CRC Press, Boca Raton, Fla., (1984)], which is incorporated herein by reference. Is incorporated. For example, the lipid-containing particles may be in the form of steroid lipid vesicles, stable flurillamela lipid vesicles (SPLV), single phase vesicles (MPV), or lipid matrix carriers (LMC). In the case of MLV, liposomes, if desired, may undergo multiple (5 or more) freeze-thaw cycles to enhance their trapped volume and trapping efficiency and provide a more uniform internal lamellae distribution of the solute. .

In one embodiment, liposomes are prepared by high temperature, high pressure homogenization, for example to reach high encapsulation efficiency (EE). Encapsulation efficiency will provide the percentage of active material that has been successfully captured / adsorbed into the nanoparticles and will be performed into the deeper layers of the skin. The major obstacles to the application of nanostructured lipid carriers (NLC) as carriers for hydrophilic active materials are the limited loading capacity (LC) and encapsulation efficiency (EE) of NLC for these molecules, and wt% EE is [(added Active material-free "non-captured active material") / added active material] * 100 (thus, for example, 5 wt% wt% EE means that 5 wt% of active material is trapped into the carrier system).

The phase transfer temperature from the gel form to the crystalline two-dimensional grid clarifies low mobility in the fluid crystalline structure. The phase transition temperature of the lipids mentioned depends on the head group, chain length and ester saturation levels of the fatty acids. The temperature can be -20 ° C to 60 ° C and can be established by thermal analysis method. It is embedded in the fluid crystal phase to increase the mobility of the lipophilic agent and to exchange positions within the lipid layer, but does not discard the lipid layer [46].

The physical structure of the multilayer layer system will be formed throughout the interaction between phospholipids and aqueous media by high pressure homogenization and dehydration of dry lipids. In this way a multilayer container (MLV) is constructed. Polycarbonate membranes of size 10-500 nm will be used for liposome extrusion. Homogenization and size will be determined throughout the pore diameter of the filter and the number of extrusion steps. It will aim to reach the highest encapsulation efficiency.

The use of this carrier system has inherent physicochemical properties different from bulk materials of the same composition, such as extremely small sizes (small particles in the 1-100 nm dimensional range), large surface area, and high reactivity to mass ratios. These properties are being used to overcome the limitations of skin penetration with larger sized molecules and to encapsulate lipophilic and hydrophilic materials as needed to cross the skin barrier.

In a further aspect the present invention relates to suitable formulations of the compositions of the present invention for topical or transdermal application.

The compositions of the present invention can be used for different types of topical or transdermal application, which can be in solid, liquid or semisolid form. Thus, suitable formulations include, but are not limited to, emulsions (eg oils and / or silicones in water emulsions, water-in-oil and / or silicone emulsions, water / oil / water or water / silicone / water type emulsions, and oils / water / Oil or silicone / water / silicone type emulsions), microemulsions, aqueous dispersions, oils, milks, balms, foams, aqueous or oily lotions, aqueous or oily gels, creams, solutions, hydroalcoholic solutions, hydroglycolic solutions, Inclusion of the compositions of the invention in hydrogels, serums, ointments, mousses, pastes, sprays or aerosols as well as any transdermal patches. In typical transdermal therapeutic systems such as patches or pads, the compositions of the invention (with or without at least one adjuvant) are embedded in combination with penetration enhancers and / or crystallization inhibitors, if desired. Thus, in certain embodiments the composition is in the form of a cream or gel or lotion, and in other specific embodiments the composition is in the form of a transdermal therapeutic system such as a patch or pad.

In a further aspect, the present invention relates to the prevention and / or treatment of skin light damage symptoms, in particular skin atrophy, skin pigmentation (patches / spots), photodermatitis (erythema: skin inflammation and redness), capillary dilator (Copprose) ) And the use of the compositions (and formulations thereof) of the invention to protect the skin from the sun, UVA and UVB radiation, as well as in the prevention and / or treatment and prevention of actinic keratosis.

Accordingly, the invention is an amount effective to stop the process of photodamage, that reactive oxygen species ROS, hyper-oxide O ^-2 and nitric oxide (NO), and therefore cytotoxic peroxy nitrate (ONOO ^-) an amount effective to inhibit the accumulation of As such, a method of preventing and / or treating optical damage to a skin of a subject comprising administering to the subject a composition of the invention (and a topical formulation thereof) is contemplated.

The composition (or formulation thereof) may be administered as needed at regular intervals (eg, once, twice or several times a day) or in essentially continuous manner (eg, via a transdermal patch).

The following examples are representative examples of the invention without limiting the scope of the invention.

Example

Method and substance

The dried phospholipid is dispersed at room temperature in an aqueous solution that spontaneously forms spherical colloids. 7-DHC of purity 98.7% (hplc; zone%) is liquefied at a temperature between 140 and 150 ° C. Propylene glycol was added to the liquefied 7-DHC and the resulting mixture was mixed with the phospholipid colloid under vigorous stirring at room temperature to give a colloid which forms a sphere of 20-150 nm with the addition of 7-DHC on the oil of the colloid. HA (2% low molecule 4 KDa 96.8% purity, 0.5wt% intermediate molecule 48.3KDa 97.3% purity and 0.5 wt% high molecule 1.78Х10 ⁶ Da purity 100% eye drop grade) dispersed / dissolved in water under stirring And separately added under stirring at room temperature. The HA mixture is added to the phospholipid colloid already filled with 7-DHC and stirred at room temperature for 20 minutes to obtain spontaneous formation of a homogeneous hydrogel. Microscopic analysis showed spherical particles of 20-150 nm size. Hydrogels were macroscopic and HPLC analysis showed the same concentration of 7-DHC added over 6 months and was stable.

A 7-DHC of 98.7% purity (hplc; area%) was used for the lipid phase (liquefied at temperatures between 140 and 150 ° C). Propylene glycol was used as organic solvent for 7-DHGC and phospholipids.

HA (in the form of a mixture of 2% low molecule 4 KDa 96.8% purity, 0.5 wt% intermediate molecule 48.3 KDa 97.3% purity and 0.5 wt% high molecule 1.78Х10 ⁶ Da purity 100% eye drop grade) Was used for.

Stirring at room temperature for 20 minutes resulted in spontaneous formation of a homogeneous hydrogel. Microscopic analysis showed spherical particles of 20-150 nm size.

Stability study showed high stability (≥98%) and constant content of DHC of 1.5% for 6 months in the assay (HPLC)

Example  One UV -Cream without filter system:

Example  2 UV Gel without filter system

Example  3 UV -Without filter system Serum

Example  4 UV With UV-filter system face:

Example  5 UV -Without filter system Body cosmetics ( with UV-filter system body:

Reference

Gary J. Fisher, Ph.D., Zeng Quan Wang, Ph.D., Subhash C. Datta, Ph.Djames Varani, Ph.D., Sewonkang, M.D., And John J. Voorhees, M.D. Pathophysiology Of Premature Skin Aging Induced by Ultraviolet Light The New England Journal Of Medicine December 11, 2016

2.Wound Repair and Regeneration. 15 (5): 708-17 September 2007.

3.American Academy of Dermatology, Aging Skin Net, "Causes of Aging Skin".

Matthias Wacker and Michael F. Holick Sunlight and Vitamin D A global perspective for health Dermato-Endocrinology 5: 1, 51-108; January / February / March 2013.

5. Holick MF Vitamin D deficiency ". N. Engl. J. Med. 357 (3): 266-81 July 2007.

6.Holick MF Vitamin D: the underappreciated D-lightful hormone that is important for skeletal and cellular health. Current Opinion in Endocrinology, Diabetes and Obesity. 9 (1): 87-98 February 2002.

Holick MF Sunlight and Vitamin D. Journal of General Internal Medicine. 17 (9): 733-735 September 2002.

Meghan Russell Assessing the Relationship between Vitamin D3 and Stratum Corneum Hydration for the Treatment of Xerotic Skin Nutrients 2012, 4, 1213-1218

9.Abramovits W. Calcitriol 3 microg / g ointment: an effective and safe addition to the armamentarium in topical psoriasis therapy. J Drugs Dermatol. 2009; 8 (8 Suppl): s17-22.

10. Gerritsen MJ, Van De Kerkhof PC, Langner A. Long-term safety of topical calcitriol 3 microg g (-1) ointment. Br J Dermatol. 2001; 144 Suppl 58: 17-19.

Meghan Russell Assessing the Relationship between Vitamin D3 and Stratum Corneum Hydration for the Treatment of Xerotic Skin Johnson and Johnson Skin Research Center, CPPW, Johnson & Johnson Consumer Companies, Inc., Skillman, NJ 08558, USA Nutrients 2012, 4, 1213. -1218

12.Rizova E, Corroller M. Topical calcitriol--studies on local tolerance and systemic safety. Br J Dermatol. 2001; 144 Suppl 58: 3-10.

13. Mason AR, Mason J, Cork M, Dooley G, Edwards G. Topical treatments for chronic plaque psoriasis. Cochrane Database Syst Rev. 2009 (2): CD005028.

14. Murphy G, Reich K. In touch with psoriasis: topical treatments and current guidelines. J Eur Acad Dermatol Venereol. 2011; 25 Suppl 4: 3-8.

15. vY. Oda, Y. Uchida, S. Moradian, D. Crumrine, P.M. Elias, D. D. BikleVitamin D receptor and coactivators SRC 2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation. J Invest Dermatol, 129 (2009), pp. 1367-1378

16.Jurgen Schauber, Richard L. Gallo, Antimicrobial peptides and the skin immune defense system, Journal of Allergy and Clinical Immunology, Volume 122, Issue 2, August 2008, Pages 261-266, ISSN 0091-6749

17.Burkiewicz CJ, Guadagnin FA, Skare TL, do Nascimento MM, Servin SC, de Souza GD. Vitamin D and skin repair: a prospective, double-blind and placebo controlled study in the healing of leg ulcers. Rev Col Bras Cir. 2012 Sep-Oct; 39 (5): 401-7.

18. Schauber J, Dorschner RA, Coda AB, et al. Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism. J Clin Invest. 2007; 117: 803-11.

19. Zasloff M. Sunlight, vitamin D, and the innate immune defenses of the human skin. J Invest Dermatol. 2005; 125: xvi-xvii.

20. J.D. Heilborn, M. F. Nilsson, G. Kratz, G. Weber, O. Sørensen, N. Borregaard, et al. The cathelicidin anti-microbial peptide LL-37 is involved in re-epithelialization of human skin wounds and is lacking in chronic ulcer epithelium J Invest Dermatol, 120 (2003), pp. 379-389.

21. De Haes P, Garmyn M, Verstuyf A et al. Two 14-epi analogues of 1,25-dihydroxyvitamin D3 protect human keratinocytes against the effects of UVB. Arch Dermatol Res 2004: 12: 527-534

22. De Haes P, Garmyn M, Carmeliet G et al. Molecular pathways involved in the anti-apoptotic effect of 1,25-dihydroxyvitamin D3 in primary human keratinocytes. J Cell Biochem 2004: 93: 951-967.

23.De Haes P, Garmyn M, Degreef H, Vantieghem K, Bouillon R, Segaert S. 1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes. J Cell Biochem 2003: 89: 663-673.

24. Wong G, Gupta R, Dixon K M et al. 1,25-Dihydroxyvitamin D and three low-calcemic analogs decrease UV-induced DNA damage via the rapid response pathway. J Steroid Biochem Mol Biol 2004: 89-90: 567-570.

25. De Haes P, Garmyn M, Verstuyf A et al. 1,25-Dihydroxyvitamin D3 and analogues protect primary human keratinocytes against UVB- induced DNA damage. J Photochem Photobiol B 2005: 78: 141-148

26. Reichrath, Jorg. Vitamin D and the skin: an ancient friend, revisited. Experimental dermatology, 2007, 16. Jg., Nr. 7, S. 618-625

27.Kielty CM, Whittaker SP, Grant ME, Shuttleworth CA. Type VI collagen microfibrils: evidence for a structural association with hyaluronan. J Cell Biol. 1992; 118: 979-90

28. Baccarani-Contri M, Vincenzi D, Cicchetti F, Mori G, Pasquali-Ronchetti I. Immunocytochemical localization of proteoglycans within normal elastin fibers. Eur J Cell Biol. 1990; 53: 305-12

29. Cleland RL, Wang JL. Ionic polysaccharides. 3.Dilute solution properties of hyaluronic acid fractions. Biopolymers. 1970; 9: 799-810

30. Bhattacharya J, Cruz T, Bhattacha-rya S, Bray BA. Hyaluronan affects extravascular water in lungs of un- anesthetized rabbits. J Appl Physiol. 1989; 66: 2595-9

fer-Korting M, Korting HC. Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects. Skin Pharmacol Physiol. 2004;17:207-1331.Weindl G, Schaller M, Sch

fer-Korting M, Korting HC. Hyaluronic acid in the treatment and prevention of skin diseases: molecular biological, pharmaceutical and clinical aspects. Skin Pharmacol Physiol. 2004; 17: 207-13

32. Turino GM. The lung parenchyma--a dynamic matrix. (J. Burns Amberson lecture). Am Rev Respir Dis. 1985; 132: 1324-34

33. Robert A. Greenwald And Wai W. Moy Effect Of Oxygen-Derived Free Radicals On Hyaluronic Acid Arthritis And Rheumatism, Vol. 23, No. 4 (April 1980)

34.Eleni Papakonstantinou, Michael Roth and George Karakiulakis Hyaluronic acid A key molecule in skin aging. Dermato-Endocrinology 4: 3, 253-258; July-December 2012.

35.Foschi D1, Castoldi L, Radaelli E, Abelli P, Calderini G, Rastrelli A, Mariscotti C, Marazzi M, Trabucchi E. Hyaluronic acid prevents oxygen free-radical damage to granulation tissue: a study in rats. Int J Tissue React. 1990; 12 (6): 333-9.

36.Celebi S1, Tepe C, Yelken K, Celik O. Efficacy of dexpanthenol for pediatric post-tonsillectomy pain and wound healing. Ann Otol Rhinol Laryngol. 2013 Jul; 122 (7): 464-7.

37.Siddharth Mukherjee, Abhijit Date, Vandana Patravale, Hans Christian Korting, Alexander Roeder, Gunther Weindl Retinoids in the treatment of skin aging: an overview of clinical effi cacy and safety Clinical Interventions in Aging 2006: 1 (4) 327-348.

38. Wohlrab J1, Kreft D. Niacinamide-mechanisms of action and its topical use in dermatology. Skin Pharmacol Physiol. 2014; 27 (6): 311-5.

39. Biro K1, Thai D, Ochsendorf FR, Kaufmann R, Boehncke WH. Efficacy of dexpanthenol in skin protection against irritation: a double-blind, placebo-controlled study. Contact Dermatitis. 2003 Aug; 49 (2): 80-4.

rgen Br

ck, Julia Lenz, Steffi B

chs, Thomas T

ting. Peripheral CD8+ T Cell Tolerance Against Melanocytic Self-Antigens in the Skin Is Regulated in Two Steps by CD4+ T Cells and Local Inflammation: Implications for the Pathophysiology of Vitiligo. Journal of Investigative Dermatology Volume 124, Issue 1, January 2005, Pages 144-150.40.Julia Steitz, J

rgen Br

ck, Julia Lenz, Steffi B

chs, Thomas T

ting. Peripheral CD8 + T Cell Tolerance Against Melanocytic Self-Antigens in the Skin Is Regulated in Two Steps by CD4 + T Cells and Local Inflammation: Implications for the Pathophysiology of Vitiligo. Journal of Investigative Dermatology Volume 124, Issue 1, January 2005, Pages 144-150.

b F, Wenck H, Gallinat S. A novel treatment option for photoaged skin. J Cosmet Dermatol. 2008 Mar;7(1):15-22. 41.Knott A1, Koop U, Mielke H, Reuschlein K, Peters N, Muhr GM, Lenz H, Wensorra U, Jaspers S, Kolbe L, Raschke T, St

b F, Wenck H, Gallinat S. A novel treatment option for photoaged skin. J Cosmet Dermatol. 2008 Mar; 7 (1): 15-22.

42.The American Society of Health-System Pharmacists. Retrieved 8 December 2016.

43. WHO Model Formulary 2008 (PDF). World Health Organization. 2009. p. 496.ISBN 9789241547659.Retrieved 8 December 2016.

44.Prockop DJ, Kivirikko KI (1995). "Collagens: molecular biology, diseases, and potentials for therapy". Annu. Rev. Biochem. 64: 403-34.

45. Peterkofsky B (December 1991). "Ascorbate requirement for hydroxylation and secretion of procollagen: relationship to inhibition of collagen synthesis in scurvy". Am. J. Clin. Nutr. 54 (6 Suppl): 1135S-1140S.

R (1985). "Post-translational processing of procollagens". Annals of the New York Academy of Sciences. 460: 187-201.46.Kivirikko KI, Myllyl

R (1985). "Post-translational processing of procollagens". Annals of the New York Academy of Sciences. 460: 187-201.

47. Rebouche CJ (December 1991). "Ascorbic acid and carnitine biosynthesis". Am. J. Clin. Nutr. 54 (6 Suppl): 1147S-1152S. PMID 1962562.

48. Dunn WA, Rettura G, Seifter E, Englard S (September 1984). "Carnitine biosynthesis from gamma-butyrobetaine and from exogenous protein-bound 6-N-trimethyl-L-lysine by the perfused guinea pig liver.Effect of ascorbate deficiency on the in situ activity of gamma-butyrobetaine hydroxylase" (PDF). J. Biol. Chem. 259 (17): 10764-70. PMID 6432788.

49. Padayatty SJ, Katz A, Wang Y, Eck P, Kwon O, Lee JH, Chen S, Corpe C, Dutta A, Dutta SK, Levine M (February 2003). "Vitamin C as an antioxidant: evaluation of its role in disease prevention". J Am Coll Nutr. 22 (1): 18-35. doi: 10.1080 / 07315724.2003.10719272. PMID 12569111.Archive from the original on July 21, 2010.

50. Traber MG, Stevens JF; Stevens (2011). "Free Radical Biology and Medicine-Vitamins C and E: Beneficial effects from a mechanistic perspective". Free Radical Biology and Medicine. 51 (5): 1000-13 2011.

Claims (15)

A composition comprising at least one vitamin D3 or precursor or derivative thereof and at least one hyaluronic acid or derivative thereof encapsulated in a lipid based colloidal carrier system. The composition of claim 1, wherein the vitamin D3 precursor is 7-DHC or a derivative thereof. The composition of claim 1, wherein the hyaluronic acid is a mixture of low molecular weight, medium molecular weight and high molecular weight hyaluronic acid. The method of claim 1, wherein the lipid based colloidal carrier system is liposomes, niosomes, transferosomes, microelles, nanoparticles, microemulsions and others, preferably liposomes, niosomes, transferosomes, most preferred. Preferably a liposome. The method according to any one of claims 1 to 4, selected from vitamin A, preferably retinyl palmitate, at least one vitamin B, vitamin C, preferably L-ascorbic acid and vitamin E, preferably tocopheryl acetate The composition further comprises one or more additional ingredients. The composition of claim 5, wherein the at least one vitamin B is riboflavin (vitamin B2), niacinamide (vitamin B3), dexpanthenol (provitamin B5), and / or folic acid (vitamin B9). The method of claim 1 wherein i) retinyl palmitate (vitamin A), (ii) riboflavin (vitamin B2), (iii) niacinamide (vitamin B3), (iv) dexpanthenol (provitamin B5), (v) folic acid (Vitamin B9), (vi) L-ascorbic acid (vitamin C) and (vii) tocopheryl acetate (vitamin E). The composition of claim 1, further comprising at least one UV-filter. The composition of claim 1, further comprising at least one adjuvant selected from surfactants, emulsifiers, emollients, thickeners, conditioning preservatives, buffers, wetting agents, fragrances. The method of claim 9, wherein the surfactant is polycarbonate, polyvinylpyrrolidone (PVP), polyvidone, ovidonmembranes, povidone, copovidone, hypromellose or Eudragit EPO. Composition. 10. The composition of claim 9, wherein the surfactant is polysorbate 10-150, preferably polysorbate PS20 such as Alkest TW 20 and Tween 20. The method of claim 1, wherein the lipid based colloidal carrier system consists of one or more components selected from phospholipids, lecithins, sphingomyelin, linolenic acid, linoleic acid, phosphatidylcholine and caprylic / capric triglycerides. Composition. As a topical formulation comprising a composition according to claim 1,
Solid, liquid or semisolid forms, preferably emulsions, microemulsions, aqueous dispersions, oils, milks, balms, foams, aqueous or oily lotions, aqueous or oily gels, creams, solutions, hydroalcoholic solutions, hydroglycolic solutions, Topical formulation in the form of a hydrogel, serum, ointment, mousse, paste, spray or aerosol, or transdermal patch. Use of the composition according to claims 1 to 12 or the topical formulation according to claim 14 for photoinjury (such as sun-induced inflammatory and reddening skin) skin atrophy, skin pigmentation (patch / spot), photodermatitis (erythema: inflammatory And reddened skin), capillary dilemma (couperose), skin disorders, inflammatory skin, as eczema, rosacea, atopic dermatitis, psoriasis prevention and / or treatment, and photodermatitis (Erythema), the use of a composition according to claims 1 to 12 or a topical formulation according to claim 14 for use in the prevention of actinic keratosis. A method of preventing and / or treating photodamage of a skin of a subject,
To prevent and / or treat photodamage (such as sun-induced damage), in particular skin atrophy, skin pigmentation (patches / spots), photodermatitis (erythema: inflammatory and reddening skin), capillary dilator (Copprose) Prophylactic, comprising administering to the subject a composition according to claims 1 to 12 or a topical formulation according to claim 13 in an amount effective for the prevention and / or treatment of a) and for the prevention of actinic dermatitis (erythema), actinic keratosis. And / or method of treatment.

Images